Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells

Abstract

In this study, we demonstrated that hypoxic conditions stimulated an increase in tunneling nanotube (TNT) formation in chemoresistant ovarian cancer cells (SKOV3, C200). We found that suppressing the mTOR pathway using either everolimus or metformin led to suppression of TNT formation in vitro, verifying TNTs as a potential target for cancer-directed therapy. Additionally, TNT formation was detected in co-cultures including between platinum-resistant SKOV3 cells, between SKOV3 cells and platinum-chemosensitive A2780 cells, and between SKOV3 cells cultured with benign ovarian epithelial (IOSE) cells; these findings indicate that TNTs are novel conduits for malignant cell interactions and tumor cell interactions with other cells in the microenvironment. When chemoresistant C200 and parent chemosensitive A2780 cells were co-cultured, chemoresistant cells displayed a higher likelihood of TNT formation to each other than to chemosensitive malignant or benign epithelial cells. Hypoxia-induced TNT formation represents a potential mechanism for intercellular communication in ovarian cancer and other forms of invasive refractory cancers.

Intercellular transfer of HLA‐G: its potential in cancer immunology

“…The biogenesis and release of exosomes could be impaired by dimethyl amiloride and inactivation of the small GTP‐binding protein ARF6, respectively . Additionally, the formation of TnTs could be inhibited by mTOR signalling inhibitors metformin and everolimus, and cytoskeletal inhibitors docetaxel and latrunculin A as previously reported . Second, post‐transcriptional RNA interference by HLA‐G‐specific miRNAs (such as miR‐148, miR‐152, miR‐548q and miR‐628‐5p) has been demonstrated to reduce HLA‐G expression and recover NK cell lysis of tumor cells .…”

“…70,71 Additionally, the formation of TnTs could be inhibited by mTOR signalling inhibitors metformin and everolimus, and cytoskeletal inhibitors docetaxel and latrunculin A as previously reported. 72,73 Second, post-transcriptional RNA interference by HLA-G-specific miRNAs (such as miR-148, miR-152, miR-548q and miR-628-5p) has been demonstrated to reduce HLA-G expression and recover NK cell lysis of tumor cells. 74 Third, the masking of either HLA-G or receptor ILTs with specific blocking antibodies could be a promising strategy for HLA-G/ILTs-based target therapy.…”

Partial Oxygen Pressure Affects the Expression of Prognostic Biomarkers HIF‐1 Alpha, Ki67, and CK20 in the Microenvironment of Colorectal Cancer Tissue

“…With the development of biotechnology, the changes for some functional proteins have been revealed in CRC tissues [2–4]. Hypoxia is prognostically important in cancer therapy and it has a deep impact on malignant development of various cancers [5, 6]. HIF-1 (hypoxia inducible factor-1), a kind of hydrocarbon nuclear translators, plays an important role in oxygen homeostasis [7] and consists of two subunits, HIF-1 alpha and HIF-1 beta.…”

Lost in translation: applying 2D intercellular communication via tunneling nanotubes in cell culture to physiologically relevant 3D microenvironments

“…However, with ovarian cancer cells, there was notable heterogeneity in the rate of TNT formation among cancer cell lines and benign ovarian epithelial cells. Although platinum‐chemoresistant cells (C200 and SKOV3 cell lines) were increased over chemosensitive and normal epithelial cells (A2780 and IOSE, respectively), the mean number of TNTs formed per cell was also highest in these latter cell populations . This result could have been due to the sheer number of chemoresistant cells, leading to crowding in culture conditions that simply did not provide enough room for TNT growth.…”

“…The importance of cell cycle in the genesis of TNTs has yet to be explored. Work from our group investigating how TNTs form between cancer cells has shown that factors stimulating or suppressing TNT formation are not entirely dependent on the rate of cellular proliferation . Subtypes of TNTs have been described, including most commonly those that extend between cells located at short or long distances.…”